The objective of the proposed study focuses on the development of a targeted gene therapy approach for the treatment of melanomas. The proposed studies will examine the feasibility of targeted adenoviral vectors for treatment of metastatic melanomas. 1. To construct melanoma specific replication competent adenoviral vectors. Replication competent adenoviral vectors with their E1a early gene expression controlled by a tyrosinase promoter and containing a herpes simples virus thymidine kinase (HSV-TK) suicidal gene will be constructed. In addition, adenoviral vectors with a 15 -mer avB3. 2. To target tumor vascular endothelial cells with non-replication HSV- TK adenoviral vectors. Adenoviral vectors with a HSV-TK gene expression controlled by a VEGF receptor promoter will be engineered. Specificity of the vector will be further increased by conjugation to monoclonal antibodies that specifically react with tumor endothelial or integrin avB3. 3. To examine the effect of the targetable adenoviral vectors in vitro and in vivo. Tumor specific replication and cytopathic effect of replication competent adenoviral vectors will be tested in vitro in human melanoma and normal human cell lines, and in vivo in a nude mouse model. The specificity of adenoviral vectors targeted to tumor endothelial cells will be evaluated in vitro in primary and metastatic human melanomas with a three-dimension culture system. The efficacy of both replication competent and endothelial targeted adenoviral vectors will be examined in a chimeric human/mouse model.